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An Intracellular Serpin Regulates Necrosis by Inhibiting the Induction and Sequelae of Lysosomal Injury

2007; Cell Press; Volume: 130; Issue: 6 Linguagem: Inglês

10.1016/j.cell.2007.07.013

1097-4172

Cliff J. Luke, Stephen C. Pak, Yuko S. Askew, Terra L. Naviglia, David J. Askew, Shila M. Nobar, Anne C. Vetica, Olivia S. Long, Simon C. Watkins, Donna B. Stolz, Robert Barstead, Gary Moulder, Dieter Brömme, Gary A. Silverman,

Endoplasmic Reticulum Stress and Disease

Extracellular serpins such as antithrombin and α1-antitrypsin are the quintessential regulators of proteolytic pathways. In contrast, the biological functions of the intracellular serpins remain obscure. We now report that the C. elegans intracellular serpin, SRP-6, exhibits a prosurvival function by blocking necrosis. Minutes after hypotonic shock, srp-6 null animals underwent a catastrophic series of events culminating in lysosomal disruption, cytoplasmic proteolysis, and death. This newly defined hypo-osmotic stress lethal (Osl) phenotype was dependent upon calpains and lysosomal cysteine peptidases, two in vitro targets of SRP-6. By protecting against both the induction of and the lethal effects from lysosomal injury, SRP-6 also blocked death induced by heat shock, oxidative stress, hypoxia, and cation channel hyperactivity. These findings suggest that multiple noxious stimuli converge upon a peptidase-driven, core stress response pathway that, in the absence of serpin regulation, triggers a lysosomal-dependent necrotic cell death routine.